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Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation due to defects in the enzyme phenylalanine hydroxylase (PAH). Phe accumulation can lead to cognitive impairment. Some individuals with PKU respond to tetrahydrobiopterin (BH4) treatment, the natural cofactor of PAH, by a reduction in blood Phe concentrations. We tested 12 patients with PKU, 8–29 years of age, all carrying the common Y414C mutation in the PAH gene. Three were homozygous and nine were compound heterozygous, with the second mutation being a putative null mutation. During the study period, genuine protein was increased to approximately 1 g/kg. The patients were treated with 20, 10, and 5 mg BH4/kg/day for 1 week on each dose, starting with 20 mg/kg. A positive response was defined as a decline in blood Phe > 30%. Blood Phe was measured four times a week. Nonresponding children were excluded from the study. Eleven of 12 patients had a positive response with 20 mg/kg, 5/10 responded on 10 mg/kg, and 1/9 on 5 mg/kg. Two were late responders, with a response on 20 mg/kg after >48 h. We could confirm the previously reported inconsistent responsiveness of Y414C in the nine heterozygous patients, whereas the three homozygous patients had early median Phe declines of 73%, 51%, and 27%, respectively, on the three different doses. The varying responses despite uniform trial conditions and genotypes may be due to individual differences in BH4 absorption or metabolism. No side effects were observed.

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Abbreviations

BH4:

6R-tetrahydrobiopterin

HPA:

Hyperphenylalaninemia

MHP:

Mild hyperphenylalaninemia

PKU:

Phenylketonuria

S-Phe:

Serum phenylalanine

PAH:

Phenylalanine hydroxylase

PAH :

Phenylalanine hydroxylase gene

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Acknowledgements

We thank professor Karen Brøndum-Nielsen for critical and constructive reading of the manuscript. The study was supported by grants from The Danish Health Insurance Foundation and Else Hjort’s Fund, the widow of MSc. in engineering Stenild Hjorth.

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Authors and Affiliations

  1. Center for PKU, The Kennedy Center, Gl. Landevej 7, 2600, Glostrup, Denmark

    Jytte Bieber Nielsen, Karin E. Nielsen & Flemming Güttler

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  1. Jytte Bieber Nielsen
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  2. Karin E. Nielsen
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  3. Flemming Güttler
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Correspondence to Jytte Bieber Nielsen.

Additional information

Communicated by: John H. Walter

Competing interest: None declared.

References to electronic databases: Phenylketonuria: OMIM 261600. Phenylalanine hydroxylase: EC 1.14.16.1

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Nielsen, J.B., Nielsen, K.E. & Güttler, F. Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation. J Inherit Metab Dis 33, 9–16 (2010). https://doi.org/10.1007/s10545-009-9002-0

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  • DOI: https://doi.org/10.1007/s10545-009-9002-0

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